The transmission of excitation through nerves and the actions of main organs are performed by neurotransmitters. These neurotransmitters include a cholinergic neurotransmitter system which secrets acetylcholine caused by stimuli in the central and peripheral nervous systems, and an adrenergic transmitter system which secrets noradrenaline. Besides, there are a lot of neurotransmitters considered to be important in the central nervous system (CNS), such as dopamine, serotonin, and inhibitory GABA (γ-aminobutyric acid). Among them, the serotonin nervous system is closely related to mental illnesses such as concern, anxiety, depression, and the like. It is known that the distribution of its receptors is considerably reduced in patients with mental illness or dementia. The serotonin system in the brain is known to regulate various physiological actions and mental states as an important neurotransmission network which control behaviors and physical functions including concern and emotional anxiety.
Serotonin (5-HT) in the central nervous system has been linked with cause of many diseases and is known to be responsible for, in particular, mental diseases such as depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorders (OCD), migraine, and panic disorder. Recent advances in pharmacology, molecular biology, and genetics on the serotonin nervous system have enabled the development of improved drug therapies for treatment of specific nervous system diseases. In fact, current general treatment methods for theses diseases have been considered to work by regulating physiological activities of serotonergic materials.
In the serotonin system having various receptor subtypes, serotonin receptors activated by 5-HT were revealed to have at least 7 subtypes (5-HT1-7), which were again divided into different subtypes (A, B . . . ). The 5-HT2c serotonin receptor subtype is transcribed and expressed in hypothalamic structure associated with appetite regulation.
It has been demonstrated that the 5-HT2c receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT2c receptor, reduces food intake in mice that express the normal 5-HT2c receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2c receptor (Nature (1995), 374, 542-546). In a recent clinical study, a sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology (1997), 133, 309-312).
The 5-HT2c receptor has been suggested to be involved in CNS disorders such as depression and anxiety (IDrugs (1999), 2, 109-120).
The 5-H2c receptor has also been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs (1998), 1, 456-470).
Compounds which have a selective effect on the 5-HT2c receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.
The prior art for 5-HT2c receptor antagonists is described below.
U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorectic agent.
EP-A1-863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT2c receptor agonists having antidepressant activity and which can be used for treating or preventing serotonin-related diseases, including eating disorders and anxiety.
WO 87/04928 discloses 2-(1-piperazinyl)pyrimidines as agents for treating neuropathy.
EP-A2-226842 discloses 1,4-naphthalenedione heterocyclic derivatives as antiallergics and antiasthmatics including 2-(3-bromophenyl)-4-(1-piperazinyl)-pyrimidine.
EP-A-657 426 discloses tricyclic pyrrole derivatives having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses 1-aminoethylindoles having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
WO 00/12475 discloses indole derivatives as 5-HT2b or 5-HT2c receptor ligands, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT2c receptor agonists, particularly for the treatment of obesity.
WO 00/12482 discloses indazole derivatives as selective, directly active 5-HT2c receptor ligands, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/035922 discloses 2,3,4,4,α-tetrahydro-1H-pyrazino[1,2-α]quinoxalin-5(6H)ones as 5HT2c agonists, which may be used for the treatment of obesity.
WO 00/044737 discloses aminoalkylbenzofurans as 5-HT2c agonists, which may be used for the treatment of obesity.
However, there still remains a need for development of 5-HT2c receptor antagonists having higher affinity and selectivity for 5-HT2c receptors.
Thus, the present inventors have performed research to develop 5-HT2c receptor antagonists having higher affinity and selectivity for 5-HT2c receptors than those of the prior art, synthesized indole carboxylic acid bispyridyl carboxamide derivatives, and identified that the derivatives have high affinity and selectivity for 5-HT2c receptors, thereby leading to completion of the present invention.